MR-guided focused ultrasound is proving to be a safe, effective treatment for tumors in children and young adults.

Teams of physicians are using two modalities that are very well known to radiologists—MRI and ultrasound—to design pediatric tumor interventions that are more precise and less invasive than current methods. Among others, researchers at the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children's National Health System in Washington, D.C., and Nicklaus Children's Hospital in Miami are studying the use of MR-guided focused ultrasound (MRgFUS) for the treatment of relapsed solid tumors, benign bone tumors, and benign brain tumors in children and young adults.

Focused ultrasound is not new. According to the Focused Ultrasound Foundation, one of the first approved applications was to treat uterine fibroids in women; the application was approved by the FDA in 2004. In 2012, the FDA approved the technology for the relief of pain associated with cancer that has spread to the bone. And, in 2015, the FDA approved two focused ultrasound systems for the ablation of prostate tissue.

"You can imagine that high-intensity focused ultrasound [HIFU] would have even greater benefit in the pediatric space because it is delivered without ionizing radiation and surgery," says Peter Kim, MD, CM, PhD, vice president of the Sheikh Zayed Institute at Children's National, who leads its Image-Guided Non-Invasive Therapeutic Energy program. "As physicians, our mission is always to make pediatric care more precise, less invasive, and pain-free."

Researchers at Children's National are looking at MRgFUS, which typically uses a HIFU beam, to treat pediatric osteoid osteomas, benign tumors that usually develop in the long bones of the leg—femurs or tibias—but can occur in any bone. Between 7% and 20% of cases occur in the spine. In most cases, osteoid osteomas are small—less than 2 cm. The tumors are painful, says Karun Sharma, MD, PhD, director of IR at Children's National.

"It's very classic bone pain," he says. "No trauma is associated with it. The pain happens at night, so it wakes them up." Nonsteroidal anti-inflammatory drugs (NSAIDs) can provide some relief, but it is temporary, Sharma says. "This pain can last for years and years, and we don't want to give kids or adolescents strong doses of NSAIDs for that long because of all the side effects."

In the '70s and '80s, surgeons would scrape the tumor from the bone or remove the affected part of the bone. The surgery would often result in collateral damage "and patients often had to be on crutches and bed rest for a long time," Sharma says. In the '90s, radiofrequency ablation (RFA) became a better option. While RFA is less invasive than surgery, it still requires drilling through muscle and soft tissue into bone. "It is a very good treatment and 90% to 95% effective," he says.

Pushing the Envelope
Two years ago, the researchers at Children's National wanted to "push the envelope" and so they began trials to see whether MRgFUS would be an even better option to locally treat both benign osteoid osteomas and malignant solid tumors. The researchers have treated 12 patients. "We are very pleased with the success of the treatments so far," Sharma says. "We have been able to show that it is a very safe treatment." The next step for the osteoid osteoma study, Sharma says, is to compare MRgFUS head to head with RFA. "We suspect the results will be similar, but there are thousands of cases of RFA recorded and only 30 of MR-HIFU. We have to look at MR-HIFU more closely and in more detail."

The clinical trial in solid tumors, led by AeRang Kim, MD, PhD, a pediatric oncologist at Children's National, also includes desmoid tumors. Desmoid tumors are benign but very locally aggressive soft tissue tumors. Their recurrence rate after surgery is high, and medical therapies have not demonstrated substantial effectiveness, AeRang Kim says.

The patients in the MRgFUS studies don't have tumors that are close to the spine or the brain. "We wouldn't want to risk any thermal or heat injury to the spinal cord," Sharma says. Tumors in the pelvis also would be hard to reach, he adds. One patient with a tumor in the inside of the pelvis had to be excluded from the osteoid osteoma trial because he couldn't be positioned in the machine to make delivering the ultrasound feasible, Sharma says.

The patients receive a CT or MRI scan prior to the procedure so that the physicians can identify the target area that needs to be heated and destroyed. Interventional radiologists who perform ablations understand how to use HIFU to heat the tissue, Sharma says. "But this is a different type of ablation, and you do have to learn how to plan the treatment and avoid any critical structures. It is something that the interventional radiologist can pick up, but there is a learning curve." MR provides real-time guidance to the tumor target, and thermal mapping allows for monitoring. The key is to cause necrosis of the tumor but not affect surrounding tissue, Sharma says.

The preplanning for this procedure is very important, Peter Kim says. "These tumors grow in size and change position, so it is important to plan the procedure accordingly. When you are focusing the energy beam, you want to make sure there aren't any critical structures between the source of the energy and the tissue." The procedure itself takes about an hour, he says.

Tumors of the bone are ideal for HIFU treatment because bone tends to absorb sound and heat very well, Peter Kim notes. "It's an ideal situation to test if it's safe." The only possible complication seen so far—and it's considered minor—is burn to the skin. Without incisions, the risk of infection from the procedure is practically nil, he says.

The researchers at Children's National also are looking at using MRgFUS to deliver a heat-activated chemotherapy. They started a phase I study in 2016, funded by the National Institutes of Health, to determine whether a safe and tolerable dose of Celsion Corporation's ThermoDox, a lyso-thermosensitive liposomal doxorubicin (LTLD), can be administered in combination with MRgFUS to treat refractory or recurrent solid tumors. Under MR guidance, the HIFU waves directly heat the tumor and the surrounding area. LTLD is administered through a vein, and the area around the tumor is heated. Upon heating, liposomes release doxorubicin at the heated tumor site allowing for targeted drug delivery.

This is the first time that LTLD is being administered in combination with MRgFUS and the first time it is being evaluated in children. The advantage to this method is that it allows for increased local concentration of chemotherapy without increasing systemic side effects. "We may increase the concentration of doxorubicin upwards of 10-fold by delivering therapy this way," says AeRang Kim, the principal investigator of the study. And by targeting the tumor precisely, it causes less damage to surrounding healthy tissue.

Brain Applications
A multidisciplinary team of researchers at Nicklaus Children's Hospital is studying MRgFUS to treat hamartoma tumors in young patients who experience tumor-associated seizures. The first procedure, performed March 7, 2017, on a 21-year-old student, was successful, says Travis Tierney, MD, PhD, the principal investigator. A postprocedure MRI showed that the student's tumor was completely ablated, and she remains seizure-free. If the tumor had been removed with open surgery, the patient would have been hospitalized for several days, required sutures, and been at risk of bleeding and infections, Tierney says. Another option is stereotactic radiation (Gamma Knife or proton beam); however, either method uses ionizing radiation, whereas HIFU does not, Tierney says. He considers HIFU to be a far better option because ionizing radiation could cause new tumors to form along the radiation path.

Also, the brain responds unpredictably to the radiation. "We've seen in a number of cases where radiation causes problems for the child in terms of cognition," Tierney says. "Depending on where their tumor is, they could lose IQ points." Each person's tumor is different. "The shapes are different, and they can be in different spots in the brain. Some are smaller and some are bigger," he says. The first case in which the team used MRgFUS was easy "because it was a small remnant of a tumor left from a previous surgery, and we were able to do it all with just one shot," he adds.

The largest volume that can be treated currently with HIFU is about 8 cm3, Tierney says. Also, the tumor has to be located in the middle of the brain, away from the skull, because skull bone is very dense, and it will heat. "If the tumor is in the middle of the brain, we can disperse the energy across the skull and avoid bone heating." Most pediatric tumors are probably not going to fall within these parameters, Tierney says, but he expects to find ways of overcoming these obstacles as more research is completed.

Another group of patients who the researchers at Nicklaus are highly interested in treating with MRgFUS are those with subependymal giant cell astrocytoma, a low-grade astrocytic brain tumor that arises within the ventricles of the brain. Nolan Altman, MD, chief of the radiology department at Nicklaus Children's Hospital, says MR-guidance allows doctors to ablate the tumor more precisely with HIFU.

"By using MR, we can do a thermography map to see how much the tissue is being heated in real time," Altman says. "When we do that, we can not only see that noninvolved areas are not being 'burned' but also that we are indeed accurately locating the area we want to ablate. We can see that in a matter of seconds, as the heat goes to the area of concern."

Coming Full Circle
That focused ultrasound is being used to treat brain tumors brings it full circle, Tierney says; in the 1940s and '50s, when focused ultrasound was being developed, the idea was to use it to destroy tumors noninvasively. "It was very much around brain tumors. That's because brain tumors required open surgery, and neurosurgeons didn't like having to remove the bone to get to the tumor, which they sometimes still couldn't reach and had to leave." Before the advent of computers and high-resolution CT scans, however, it was difficult to see where to target the sound waves.

In the 1960s, stereotactic radiation became the standard of care for brain tumors. In the '90s, Tierney worked with Hungarian-born physician and scientist Ferenc Jolesz, MD—who died in December 2014—at Brigham and Women's Hospital in Boston to develop a phased array that would allow the ultrasound to focus on one spot. Jolesz developed a device that was able to deliver focused ultrasound and used it to treat high-grade tumors, but it didn't have enough power, Tierney says. "Researchers at the University of Virginia (UV) realized that you don't need that much power to treat essential tremors, and that's how focused ultrasound has become a standard of care for movement disorders," Tierney says.

Jolesz's and the UV's work led to Insightec's development of the Exablate Neuro ultrasound transducer, which consists of 1,024 beams that generate enough heat to ablate the targeted tissue during treatment. Adults who undergo treatment for their tremors lie on the treatment bed in the MRI scanner fully conscious. Children who are treated with focused ultrasound are sedated so that they stay still. In July 2016, the FDA approved use of the ultrasound device to treat essential tremor in patients who have not responded to medication.

Those who are using MRgFUS to treat tumors in children and young adults are excited about its potential. They expect their research to take a few more years until they can claim it to be a safe and effective nonionizing, nonsurgical treatment method, but their results so far, they agree, look very promising.